The ability of cells to respond to each other and the substratum (forms of cell social behavior) is an important part of normal growth and development. Failures in these responses are believed to be involved in metastasis and the loss of contact inhibition of growth, forms of cell social behavior displayed by tumor cells. The importance of such cell surface and extracellular matrix molecules as fibronectin and collagen in the expression of cell social behavior is established. We had previously proposed that the cell surface proteoglycan, heparan sulfate, is also involved in such cell responses. We now have shown that cell surface heparan sulfate interacts with both fibronectin and collagen type I. Furthermore, cells which produce heparan sulfate that does not bind to fibronectin are unable to bind to fibronectin-coated substrata. Since the heparan sulfate from those cells still binds to collagen, as do the cells, it is clear that the binding sites on heparan sulfate for these two matrix molecules are distinct. These data support our general hypothesis that different cells make distinct types of heparan sulfate, which interact with different matrix or cell surface molecules.